Fatty acids are known as chemical enhancers in the field of transdermal delivery. Various fatty acids have been used to enhance the delivery of several drugs. The list of fatty acids used is extensive and encompasses saturated fatty acids such as capric acid, unsaturated fatty acids such as linoleic acid, and branched fatty acids C6 to C18, such as isostearic acid. Hydroxy fatty acids such as 2-hydroxyoctanoic acid are known to plasticize the skin, but they have not been explored for their effect on the skin permeation of drugs.
The effect of the different fatty acids on the permeation of drugs through skin is not well understood and it depends upon the vehicle, the drug used and the structure and concentration of the fatty acid. For example, oleic acid has been used to increase the permeability of acyclovir, tetrahydrocannabinol, mannitol and dihydroergotamine. Laurie acid has been used to increase the permeation of naloxone, dihydroergotamine and leuprolide. The enhancement ratio for naloxone's skin permeation using lauric acid as the enhancer were 150, 25, 15, 10 and 3 when the vehicle was propylene glycol, PEG 400, mineral oil, isopropanol and isopropyl myristate respectively. What is significant from the above references is the fact that the fatty acids increased the skin permeability by orders of magnitude for some drugs, whereas under similar experimental conditions the skin permeation of other compounds was not affected much at all. This supports the understanding that chemical enhancement is still more of an art than science. Therefore, the enhancement cannot be predicted from the properties of the drug and the fatty acid or that of the vehicle.
In general the skin permeation enhancement by saturated fatty acids is best for C10 and C12 fatty acids. C18 unsaturated fatty acids appear to be better than saturated ones but it is not clear that the same relationship is true for medium and low molecular weight fatty acids. In the studies trying to determine the effect of branching on skin permeation no difference was observed between branched and linear fatty acids except on some occasions. Increase in the concentration of the fatty acid in the formulation did not show a linear response either.
However, concentrations between 2 and 10% can be used to increase permeation and also to limit the skin irritation that can be caused by fatty acids.
It has now been found that the compositions of two fatty acids having different molecular weights of the present invention have a synergistic effect and increase the transdermal permeation of therapeutic agents to a surprising degree.